US5801256A - Method for the synthesis of 8-C-β-D 2'-O-(E)-cinnamoyl!glycopyranosyl-2- 2-hydroxy!propyl-7-methoxy-5-methylchromone - Google Patents
Method for the synthesis of 8-C-β-D 2'-O-(E)-cinnamoyl!glycopyranosyl-2- 2-hydroxy!propyl-7-methoxy-5-methylchromone Download PDFInfo
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- US5801256A US5801256A US08/858,741 US85874197A US5801256A US 5801256 A US5801256 A US 5801256A US 85874197 A US85874197 A US 85874197A US 5801256 A US5801256 A US 5801256A
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- Prior art keywords
- aloesinol
- methylchromone
- cinnamoyl
- hydroxy
- aloesin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates generally to a method for the synthesis of an anti-inflammatory and epithelial growth factor-inhibiting compound isolated from the Aloe barbadensis plant.
- this invention describes the synthesis of C-glycosylated 5-methylchromone, 8-C- ⁇ -D- 2'-O-(E)-cinnamoyl!glycopyranosyl-2- 2-hydroxy!propyl-7-methoxy-5-methylchromone, which has a molecular formulae of C 29 H 32 O 10 , and is referred to herein as the "540 compound.”
- Aloe is an intricate plant which contains many biologically active substances. (Cohen et al. in Wound Healing/Biochemical and Clinical Aspects, 1st ed. WB Saunders, Philadelphia (1992)). Over 300 species of Aloe are known, most of which are indigenous to Africa. Studies have shown that the biologically active substances are located in three separate sections of the aloe leaf--a clear gel filet located in the center of the leaf, in the leaf rind or cortex of the leaf and in a yellow fluid contained in the pericyclic cells of the vascular bundles, located between the leaf rind and the internal gel filet, referred to as the latex. Historically, Aloe products have been used in dermatological applications for the treatment of burns, sores and other wounds.
- One class of biologically active compounds that have been isolated from Aloe are the 5-methylchromones, which have the following general structure and conventional numbering: ##STR1## wherein R 1 is H, glucose or a derivative of glucose, R 2 is H, CH 3 , or glucose and R 3 is OH or ⁇ O.
- R 1 is H, glucose or a derivative of glucose
- R 2 is H, CH 3 , or glucose
- R 3 is OH or ⁇ O.
- Inflammation is a localized protective response elicited by injury or destruction of tissue resulting from physical trauma, microbial invasion or immune disorders, such as rheumatoid arthritis. Although inflammation is vital to the healing process, if uncontrolled, it can lead to more serious conditions. (Davis et al. (1986) Pa. Acad. Sci. 60:67; Gilfoil and Klavins (1965) Amer. J. Physiol. 208:867). Rheumatoid arthritis, for example, is a chronic and progressive inflammatory disease which affects connective tissue. It is characterized by inflammation in multiple joints and is a major cause of disability.
- Steroids can lessen both the tissue destruction and the symptoms resulting from inflammation, however, steroids frequently cause suppression of pituitary-adrenal function, immune suppression and seriously disturb fluid and electrolyte balance. In children, steroid use can prevent growth and can even cause death. (Fink (1991) Clin. Exper. Rheum. 2:9-13).
- Aloe vera a term used to describe the extract obtained from processing the entire leaf, not only reduces inflammation, but also improves wound healing.
- Davis et al. have shown that Aloe vera, a term used to describe the extract obtained from processing the entire leaf, not only reduces inflammation, but also improves wound healing.
- Davis et al. have shown that Aloe vera, a term used to describe the extract obtained from processing the entire leaf, not only reduces inflammation, but also improves wound healing.
- the anti-inflammatory/wound healing ability of Aloe vera has been attributed to a growth factor-like substance that activates the wound healing and inflammation reduction processes. (Davis et al. (1994) J. Am. Podiatric Med. Assoc.
- the present invention describes a method for the synthesis of the C-glycosylated 5-methylchromone, 8-C- ⁇ -D- 2'-O-(E)-cinnamoyl! glycopyranosyl-2- 2-hydroxy!propyl-7-methoxy-5-methylchromone (the "540 compound”) (3) from the readily available 5-methylchromone, Aloesin (1). (See Holdsworth (1972) Chromones in Aloe Species, Part I - Aloesin, PM 19(4):322-325).
- the invention provides a method for the synthesis of the 540 compound (3) comprising the steps of: reduction of the C10 carbonyl of Aloesin (1) to provide Aloesinol (2), esterification of the 2'-OH of Aloesinol (2) with cinnamoyl chloride to provide the 2'-O-cinnamoyl ester followed by methylation of the hydroxy group at C7 to yield the 540 compound.
- Aloesin (1) is present in much greater quantities in Aloe than the 540 compound (0.2% vs. 0.01% on a dry weight basis, respectively) and is easily isolated and purified, the method of this invention provides a much more efficient and cost effective means to obtain the 540 compound.
- FIG. 1 illustrates the chemical structure of various 5-methylchromones isolated from Aloe.
- the present invention includes a method for the synthesis of the C-glycosylated 5-methylchromone, 8-C- ⁇ -D- 2'-O-(E)-cinnamoyl! glycopyranosyl-2- 2-hydroxy!propyl-7-methoxy-5-methylchromone.
- This compound has been isolated from the Aloe barbadensis plant and has the following chemical structure: ##STR2##
- the 540 compound is present primarily in the leaf rind of the Aloe barbadensis plant.
- the 540 compound exhibits potent anti-inflammatory activity as measured by in vivo assays. This compound has also been shown to inhibit EGF-induced DNA synthesis in in vitro testing in epithelial cell lines.
- the isolation, purification and structural determination of the 540 compound and its activity are described in detail in related U.S. application Ser. No. 08/391,139, entitled “Cinnamoyl-C-Glycoside Chromone Isolated from Aloe barbadensis," filed Feb. 21, 1995 and U.S. application Ser. No. 08/621,178, entitled “Purification of Cinnamoyl-C-Glycoside Chromone,” filed Mar. 21, 1996, both of which are incorporated herein by reference in their entirety.
- the present invention includes a method for the synthesis of the 540 compound starting from the readily available 5-methylchromone Aloesin (1).
- Aloesin was the first chromone to be isolated from a wide variety of Aloe species. It is one of the main biologically active compounds isolated from leaf exudates and is easily isolated and purified.
- Aloe refers to the genus of plants found worldwide from the Liliaceae family of which the Aloe barbadensis plant is a species.
- a “5-methylchromone” is one of a group of aromatic compounds having the following structure and conventional numbering: ##STR3## wherein R 1 is H, glucose or a derivative of glucose, R 2 is H, CH 3 , or glucose and R 3 is OH or ⁇ O.
- R 1 is H, glucose or a derivative of glucose
- R 2 is H, CH 3 , or glucose
- R 3 is OH or ⁇ O.
- FIG. 1 is H, glucose or a derivative of glucose
- Most 5-methylchromones have a glucose or a derivative of glucose at C8 and are referred to as "C-glycosylated 5-methylchromones.”
- the general method of the present invention can be characterized as outlined in Scheme 1.
- reaction of the readily available 5-methylchromone Aloesin (1) (Holdsworth (1972) Chromones in Aloe Species, Part I - Aloesin, PM 19(4):322-325; van Wyk et al. (1994) Planta Med 61:250-253) with reducing agents, such as but not limited to metal hydrides, results in the reduction of the C10 carbonyl group to produce the C10 hydroxy 5-methylchromone Aloesinol (2).
- metal hydrides which can be used include but are not limited to metal acids, aluminum hydrides, borohydrides and selectides.
- the C10 carbonyl group of Aloesin (1) is reduced with e.g., NaBH 4 , to provide a mixture of diastereomers which is purified by reverse phase chromatography as outlined in the Example section below.
- the purified Aloesinol (2) is then treated with an activated cinnamic acid derivative including but not limited to imidazolides, esters, anhydrides, azides, halides and imides in the presence of a base to provide the 2'-O-cinnamoyl ester which is then treated with a methylating agent, preferably methyl iodide to provide the 540 compound (3).
- an activated cinnamic acid derivative including but not limited to imidazolides, esters, anhydrides, azides, halides and imides in the presence of a base to provide the 2'-O-cinnamoyl ester which is then treated with a methylating agent, preferably methyl iodide to provide the 540 compound (3).
- the cinnamic acid derivative is cinnamoyl chloride and the base is Na 2 CO 3 .
- Aloesinol (2) was synthesized by the reduction of Aloesin (1) as follows. A solution of Aloesin (1) (20 g) in methanol (175 mL) was cooled in ice bath at 0° C. followed by the addition of solid sodium borohydride (4 g). The mixture was then removed from the ice bath and stirred for 30 minutes. After 30 minutes the solvent was removed and the residue was dissolved in water (100 mL). The pH of the solution was adjusted to 6.0 (pH paper) with 1N aqueous citric acid. The product was purified by reversed phase HPLC chromatography by elution with 1 L of water followed by aqueous methanol. (Rainin Microsorb mv 86-200-E3!
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
Claims (8)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/858,741 US5801256A (en) | 1997-05-19 | 1997-05-19 | Method for the synthesis of 8-C-β-D 2'-O-(E)-cinnamoyl!glycopyranosyl-2- 2-hydroxy!propyl-7-methoxy-5-methylchromone |
PCT/US1998/009780 WO1998052934A1 (en) | 1997-05-19 | 1998-05-14 | METHOD FOR THE SYNTHESIS OF 8-C-β-D-[2'-O-(E)-CINNAMOYL] GLYCOPYRANOSYL-2-[2-HYDROXY] PROPYL-7-METHOXY-5-METHYLCHROMONE |
JP55043498A JP2001525854A (en) | 1997-05-19 | 1998-05-14 | Method for synthesizing 8-C-β-D- [2'-O- (E) -cinnamoyl] glycopyranosyl-2- [2-hydroxy] propyl-7-methoxy-5-methylchromone |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/858,741 US5801256A (en) | 1997-05-19 | 1997-05-19 | Method for the synthesis of 8-C-β-D 2'-O-(E)-cinnamoyl!glycopyranosyl-2- 2-hydroxy!propyl-7-methoxy-5-methylchromone |
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Publication Number | Publication Date |
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US5801256A true US5801256A (en) | 1998-09-01 |
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US08/858,741 Expired - Lifetime US5801256A (en) | 1997-05-19 | 1997-05-19 | Method for the synthesis of 8-C-β-D 2'-O-(E)-cinnamoyl!glycopyranosyl-2- 2-hydroxy!propyl-7-methoxy-5-methylchromone |
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US (1) | US5801256A (en) |
JP (1) | JP2001525854A (en) |
WO (1) | WO1998052934A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999034676A1 (en) * | 1998-01-12 | 1999-07-15 | Univera Pharmaceuticals, Inc. | Method of synthesis of derivatives of aloesin |
US6451357B1 (en) | 2001-02-26 | 2002-09-17 | Unigen Pharmaceuticals, Inc. | Method for purification of aloesin |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4656029A (en) * | 1984-04-17 | 1987-04-07 | L'oreal | Cosmetic composition containing aloesin as an agent for protection against sunlight and its use for skin and hair protection |
WO1996040182A1 (en) * | 1995-06-07 | 1996-12-19 | Board Of Regents, The University Of Texas System | Identification of a potent antioxidant from aloe barbadensis |
US5675000A (en) * | 1996-03-21 | 1997-10-07 | Univera Phytoceuticals, Inc. | Purification of cinnamoyl-C-glyoside chromone |
-
1997
- 1997-05-19 US US08/858,741 patent/US5801256A/en not_active Expired - Lifetime
-
1998
- 1998-05-14 WO PCT/US1998/009780 patent/WO1998052934A1/en active Application Filing
- 1998-05-14 JP JP55043498A patent/JP2001525854A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4656029A (en) * | 1984-04-17 | 1987-04-07 | L'oreal | Cosmetic composition containing aloesin as an agent for protection against sunlight and its use for skin and hair protection |
WO1996040182A1 (en) * | 1995-06-07 | 1996-12-19 | Board Of Regents, The University Of Texas System | Identification of a potent antioxidant from aloe barbadensis |
US5675000A (en) * | 1996-03-21 | 1997-10-07 | Univera Phytoceuticals, Inc. | Purification of cinnamoyl-C-glyoside chromone |
Non-Patent Citations (19)
Title |
---|
Davis et al. (1986) Proceedings of the Pa. Acad. Sci. 60:67. * |
Davis et al. (1989) J. Am. Podiatric Med. Assoc. 79:395. * |
Davis et al. (1994) J. Am. Podiatric Med. Assoc. 84:77. * |
Fink (1991) Clinical and Experimental Rheumatology 9:9. * |
Fries (1991) Journal of Rheumatology 18:6. * |
Gilfoil and Klavins (1965) Amer. J. Physiol. 208:867. * |
Gramatica et al. (1982) Tetrahedron Letters 23:2423. * |
Hart et al. (1988) Journal of Ethnopharmacology 23:61. * |
Hirata and Suga (1977) Z. Naturforsch 32c:731. * |
Holdsworth (1972) Chromones in Aloe Species, Part I Aloesin , PM 19(4):322. * |
Holdsworth (1972) Chromones in Aloe Species, Part I--Aloesin, PM 19(4):322. |
Holdsworth (1972) Chromones in Aloe Species, Part II Aloesone , PM 22(1):54. * |
Holdsworth (1972) Chromones in Aloe Species, Part II--Aloesone, PM 22(1):54. |
Paulus (1985) Arthritis and Rheumatism 28:1168. * |
Speranza et al. (1985) Phytochemistry 24:1571. * |
Speranza et al. (1986) Phytochemistry 25:2219. * |
Strickland et al. (1994) J. Investigative Dermatology 102:197. * |
van Wyk et al. (1995) Planta Med. 61:250. * |
Yagi et al. (1987) Planta medica 515. * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999034676A1 (en) * | 1998-01-12 | 1999-07-15 | Univera Pharmaceuticals, Inc. | Method of synthesis of derivatives of aloesin |
US6083976A (en) * | 1998-01-12 | 2000-07-04 | Univera Pharmaceuticals, Inc. | Method of synthesis of derivatives of aloesin |
US6451357B1 (en) | 2001-02-26 | 2002-09-17 | Unigen Pharmaceuticals, Inc. | Method for purification of aloesin |
Also Published As
Publication number | Publication date |
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WO1998052934A1 (en) | 1998-11-26 |
JP2001525854A (en) | 2001-12-11 |
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